Can Accelerated Reactions in Droplets Guide Chemistry at Scale?

Abstract

Mass spectrometry (MS) is used to monitor chemical reactions in droplets. In almost all cases, such reactions are accelerated relative to the corresponding reactions in bulk, even after correction for concentration effects, and they serve to predict the likely success of scaled‐up reactions performed in microfluidic systems. The particular chemical targets used in these test studies are diazepam, atropine and diphenhydramine. In addition to a yes/no prediction of whether scaled‐up reaction is possible, in some cases valuable information was obtained that helped in optimization of reaction conditions, minimization of by‐products, and choice of catalyst. In a variant on the spray‐based charged droplet experiment, the Leidenfrost effect was used to generate larger, uncharged droplets and the same reactions were studied in this medium. These reactions were also accelerated but to smaller extents than in microdroplets, and they gave results that correspond even more closely to microfluidics data. The fact that MS was also used for online reaction monitoring in the microfluidic systems further enhances the potential role of MS in exploratory organic synthesis.

State-of-the-art mass spectrometry for point-of-care and other applications: A hands-on intensive short course for undergraduate students

“…34 Students then analyzed the accelerated Leidenfrost material by MS and compared the results to those for the bulk reaction mixture ( Figure 4c and 4d). The different known methods of accelerating reaction [35][36][37][38] were discussed with the students, as was the contribution reaction acceleration could have on small scale synthesis.…”

On‐line reaction monitoring by mass spectrometry, modern approaches for the analysis of chemical reactions

“…However, a potential limitation of the use of electrospray droplets as accelerated reaction systems is that the reaction profile may have a limited relationship to the same reaction at a much larger scale. This limitation and the advantages of rapid synthesis development and the efficiency of a combined reactor and analytical system have been investigated and discussed . In this study the question of whether the droplet reactor can be used to predict chemical reactivity in flow chemistry (microfluidic) systems has been discussed in detail and evaluated using several reactions.…”

“…This limitation and the advantages of rapid synthesis development and the efficiency of a combined reactor and analytical system have been investigated and discussed. 47 In this study the question of whether the droplet reactor can be used to predict chemical reactivity in flow chemistry (microfluidic) systems has been discussed in detail and evaluated using several reactions. The authors clearly recognize that it may not be possible to transfer fully optimized reaction conditions from the droplet reactor to microfluidic scale.…”

Mass spectrometric directed system for the continuous-flow synthesis and purification of diphenhydramine

“…Another significant aspect of this work is the utilization of MS as a reaction screening module by accelerating reactions in charged microdroplets for high throughput reaction screening. 38 , 39 The acceleration factors vary from 10 2 to 10 6 allowing accelerated access to slow reactions; reaction acceleration is due to increases in reagent concentration as solvent evaporates, pH effects, and interfacial effects. 38 , 40 – 42 It is important to note that MS under the appropriate conditions can be used to either monitor or accelerate reactions.…”